TWI397530B - Substituted triazolopyridines and analogs thereof - Google Patents

Description

Substituted triazolopyridine and its analogues

The present invention relates to substituted triazolopyridines and the like, the use of the compounds as phosphodiesterase 10 (PDE10) inhibitors for the treatment of PDE10-regulated lesions, and pharmaceutical compositions comprising the same .

The present application claims priority to US Provisional Application No. 61/167,310, filed on Apr. 7, 2009.

PDE10 is known to be a dual cAMP/cGMP phosphodiesterase; see, for example, Kehler, et al., "The potential therapeutic use of phosphodiesterase 10 inhibitor", Expert Opin. Ther. Patents (2007) 17(2): 147- 158.

PDE10 is highly expressed in all striatum medium-sized spine neurons (MSN), but its performance in the brain and its surroundings is much lower or undetectable. By increasing the levels of cAMP and cGMP in all striatum MSN, inhibition of PDE10 would mimic the D2 dopamine receptor antagonism in the indirect striatum globus pallidus export pathway and increase the activity of the direct striatum nigral output pathway. In turn, the striatum output that is characteristic of schizophrenia is completely restored to normal. By increasing cortical striatal transmission, inhibition of PDE10 will improve cognitive dysfunction that is characteristic of schizophrenia. In addition, PDE10 can be dispersed to improve side effects: typical side effects include cone outer diameter symptoms, diabetes, weight gain, hyperprolactinemia, sedation, and QT _c prolongation.

PDE10 inhibitors have been reported to be useful in the treatment of other CNS (central nervous system) disorders such as psychosis, cognitive disorders (eg Alzheimer's), bipolar disorder, depression, diet-induced obesity, diabetes and Metabolic syndrome.

Papaverine is known to be a PDE10 inhibitor and has been shown to be effective in animal models of cognitive impairment.

The 8-substituted triazolopyridine phosphodiesterase 4 inhibitors useful in the treatment of skin disorders are described in WO 2008/125111. The triazolopyridine substituted with 6,7-di-aryl/heteroaryl is described in US 2006/0287324. The 6-aminomethyl substituted triazolopyridine and its derivatives are described in WO 2007/113226. Imidazo-and triazolopyridine keratin dyed compounds are described in US 2005/0229333. Imidazo- and triazolopyridines useful in the treatment of diseases associated with 11-beta-hydroxysteroid dehydrogenase type I are described in WO 2006/135795. Imidazopyridines having phospholipid creatinine 3 kinase inhibitory activity are described in EP 1277754.

In several of its embodiments, the present invention provides a novel substituted triazolopyridine PDE10 inhibitor compound and a derivative thereof represented by Formula I below, comprising one or more pharmaceutical combinations of such compounds as Formula I And a pharmaceutical composition comprising the compound of formula I or a pharmaceutical composition comprising the compound for treating a disease modulated by a PDE10 inhibitor (eg, CNS lesions, such as schizophrenia, psychosis, cognitive dysfunction (eg, Alzheimer's disease) Methods of bipolarity, depression, diet-induced obesity, diabetes, and metabolic syndrome.

The novel compound of formula I of the invention has the following structural formula:

Or a pharmaceutically acceptable salt thereof, wherein -XY- is -N=C(R ⁴ )-, -C(R ⁴ )=N- or -C(R ⁴ )=C(R ⁴ )-; R ¹ H , halogen, alkyl, alkoxy, —CF ₃ , cycloalkyl, alkoxyalkoxy, OH, hydroxyalkyl, —OCF ₃ , —O—cycloalkyl, benzyloxy, —C(O) O-alkyl-, -O-alkyl-CO ₂ H, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -alkyl N(R ⁶ ) ₂ , -NR ⁶ -C (O)N(R ⁶ ) ₂ , -N(R ⁶ )C(O)Oalkyl, -N(R ⁶ )SO ₂ -alkyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ⁶ , -SR ⁶ , trimethyldecylphenyl, aryl, -C≡C-CH ₂ OH, -C≡C-aryl, aralkyl-, -C(O)NHCH ₂ -aryl, Heteroaryl, -C≡C-heteroaryl, heteroaralkyl-, -C(O)NHCH ₂ -heteroaryl, or R ^1A is H, halogen, alkyl, alkoxy, -CF ₃ , cycloalkyl, alkoxyalkoxy, OH, hydroxyalkyl, -OCF ₃ , -O-cycloalkyl, benzyloxy, - C(O)Oalkyl, -O-alkyl-CO ₂ H, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -alkyl N(R ⁶ ) ₂ , -NR ⁶ -C(O)N(R ⁶ ) ₂ , -N(R ⁶ )C(O)Oalkyl, -N(R ⁶ )SO ₂ -alkyl, CN, -SF ₅ , -OSF ₅ ,- SO ₂ R ⁶ , -SR ⁶ , trimethyldecylphenylphenyl, -C≡C-CH ₂ OH, -C≡C-aryl, or aralkyl-; Q-system -O-, -N(R ¹⁰ ) -, -S-, -SO-, -SO ₂ - or -CH ₂ -; Z system: -(CH(R ² )) _n -(CH(R ^2A )) _m -, Substituted by 1 or 2 alkyl groups, or Substituted by 1 or 2 alkyl groups, wherein the G series -N(R ⁸ )-, -O- or -S-; or -N(R ⁵ )- together with -Z- form a 4 to 7 membered ring

It is optionally substituted with 1 or 2 alkyl groups; n is 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q is 0, 1, 2 or 3; each R ² is independently Selected as a group consisting of H, alkyl or cycloalkyl; each R ^2A is independently selected from H, alkyl, cycloalkyl, fluoro, OH, alkoxy, -N(R ⁸ ) ₂ or -alkyl a group of -N(R ⁸ ) ₂ ; R ³ is selected from the group consisting of pyridine, pyrazine,

versus a group consisting of; each R ⁴ is independently selected from the group consisting of H, alkyl, cycloalkyl, halogen, -CF ₃ , alkoxyalkyl, heteroaryl, -CN, hydroxyalkyl, aryl, aralkyl- a group of heteroaralkyl-, -OCF ₃ , -SF ₅ , -OSF ₅ and -N(R ⁶ ) ₂ ; R ⁵ is H, alkyl or cycloalkyl; each R ⁶ is independently selected from a group consisting of H, alkyl, cycloalkyl and aralkyl; R ⁷ is independently selected from H, halogen, alkyl, alkoxy, -CF ₃ , cycloalkyl, alkoxyalkoxy, OH, Hydroxyalkyl, -OCF ₃ , -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO ₂ H, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -alkyl N(R ⁶ ) ₂ , -NR ⁶ -C(O)N(R ⁶ ) ₂ , -N(R ⁶ )C(O)Oalkyl, -N( 1 or 2 substituents of the group consisting of R ⁶ )SO ₂ -alkyl, phenyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ₆ , -SR ⁶ and trialkyldecylalkyl; ⁸ is independently selected from the group consisting of H and alkyl; R ⁹ is independently selected from 1 to 3 substituents of the group consisting of H and alkyl, and when Q is -CH ₂ -, R ⁹ can also be Halogen, OH, alkoxy or -CF ₃ ; and R ^{10 -} series H, alkyl, -C(O)N(R ⁶ ) ₂ , -C(O)Oalkyl, or -SO ₂ -alkyl group.

The invention also relates to a pharmaceutical composition comprising at least one compound of formula I or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.

In another embodiment, the invention relates to a condition modulated by PDE10 (eg, CNS lesions such as: schizophrenia, psychosis, cognitive dysfunction (eg, Alzheimer's disease), bipolar disorder, A method of depression, diet-induced obesity, diabetes, and metabolic syndrome, comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a condition modulated by PDE10 (eg, CNS lesions, such as schizophrenia, psychosis, cognitive dysfunction (eg, Alzheimer's disease), bipolar disorder, depression, A method of diet-induced obesity, diabetes, and metabolic syndrome comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical composition.

The present invention also provides a novel PDE10 inhibitor compound represented by Formula II, a derivative thereof, a pharmaceutical composition comprising one or more compounds of Formula II, and a pharmaceutical composition comprising the compound of Formula II or a compound comprising the same, for treating PDE10 Inhibitor-regulated lesions (eg, CNS lesions such as schizophrenia, psychosis, cognitive dysfunction (eg, Alzheimer's disease), bipolar disorder, depression, diet-induced obesity, diabetes, and metabolic syndrome) The method.

The novel compound of formula II of the present invention has the following structural formula:

Or a pharmaceutically acceptable salt thereof, wherein p is 1, 2 or 3; R ¹¹ is H, alkyl or cycloalkyl; R ^{12 is} independently H, alkyl or cycloalkyl; and R ¹³ is selected from pyridine, pyr Oxazine,

a group consisting of; R ¹⁴ is H, alkyl, cycloalkyl or aralkyl; R ¹⁵ is independently selected from H, halogen, alkyl, alkoxy, -CF ₃ , cycloalkyl, alkoxyalkoxy Base, OH, hydroxyalkyl, -OCF ₃ , -O-cycloalkyl, benzyloxy, -C(O)Oalkyl, -O-alkyl-CO ₂ H, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ ) ₂ , -alkyl N(R ¹⁴ ) ₂ , -NR ¹⁴ -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)Oalkyl 1 or 2 substitutions of a group consisting of -N(R ¹⁴ )SO ₂ -alkyl, phenyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ¹⁴ , -SR ¹⁴ and trimethyldecyl R ¹⁶ is independently selected from the group consisting of H, halogen, alkyl, alkoxy, -CF ₃ , cycloalkyl, alkoxyalkoxy, OH, hydroxyalkyl, -OCF ₃ , -O-cycloalkyl , benzyloxy, -C(O)Oalkyl, -O-alkyl-CO ₂ H, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ ) ₂ , -alkyl N(R ¹⁴ ) ₂ , -NR ¹⁴ -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)Oalkyl, -N(R ¹⁴ )SO ₂ -alkyl, phenyl, CN, 1, 2 or 3 substituents of the group consisting of -SF ₅ , -OSF ₅ , -SO ₂ R ¹⁴ , -SR ¹⁴ and trimethyldecylalkyl; R ¹⁷ is independently selected from H, halogen, alkyl, alkoxy, -CF _3, cycloalkyl, alkoxyalkyl Group, OH, hydroxyalkyl, -OCF _3, -O- cycloalkyl, benzyloxy, -C (O) O-alkyl, -O- alkyl _{-CO 2 H, -C (O)} N (R ¹⁴ ) ₂ , -N(R ¹⁴ ) ₂ , -alkyl N(R ¹⁴ ) ₂ , -NR ¹⁴ -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)Oalkyl 1 or 2 substitutions of a group consisting of -N(R ¹⁴ )SO ₂ -alkyl, phenyl, CN, -SF ₅ , -OSF ₅ , -SO ₂ R ¹⁴ , -SR ¹⁴ and trimethyldecyl And R ¹⁸ H, alkyl, cycloalkyl, halogen, -CF ₃ , alkoxyalkyl, heteroaryl, -CN, hydroxyalkyl, aryl, aralkyl-, heteroarylalkyl- , -OCF ₃ , -SF ₅ , -OSF ₅ or -N(R ⁶ ) ₂ ; the invention also relates to a pharmaceutical composition comprising at least one compound of formula II or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier .

In another embodiment, the invention relates to a condition modulated by PDE10 (eg, CNS lesions, such as schizophrenia, psychosis, cognitive dysfunction (eg, Alzheimer's disease), bipolar disorder, depression, A method of diet-induced obesity, diabetes, and metabolic syndrome, comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound of Formula II or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a condition modulated by PDE10 (eg, CNS lesions, such as schizophrenia, psychosis, cognitive dysfunction (eg, Alzheimer's disease), bipolar disorder, depression, A method of diet-induced obesity, diabetes, and metabolic syndrome, comprising administering to a mammal in need of such treatment a medicament comprising a medically effective amount of at least one compound of Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier combination.

In one embodiment of the invention, the compound has the structural formula I.

In one case in Formula I, -XY- based -C (R ⁴⁾ = N- embodiment.

In one embodiment of Formula I, -XY- is -N=C(R ⁴ )-.

In Formula I one embodiment, -XY- based ^{-C (R 4) = C (} R 4) -.

In one embodiment of Formula I, Z is -(CH(R ² )) _n -(CH(R ^2A )) _m -.

In one embodiment of Formula I, Z-(CH(R ² )) _n -(CH(R ^2A )) _m - and the sum of n and m is from 1 to 3, preferably from 2 to 3.

In one embodiment of formula I, Z is -(CH(R ² )) _n -(CH(R ^2A )) _m -; R ² is H or alkyl, preferably H or methyl, more preferably H; and R ^2A is H or an alkyl group, preferably H or methyl, more preferably H.

In one embodiment of Formula I, the Z system is -(CH(R ² )) _n -(CH(R ^2A )) _m -; the sum of n and m is from 1 to 3, preferably from 2 to 3; ² is H or an alkyl group, preferably H or a methyl group, more preferably H; and R ^2A is H or an alkyl group, preferably H or a methyl group, more preferably H.

In one embodiment of formula I, R ¹ is H, halo, heteroaryl, aryl or -C≡C-CH ₂ OH, wherein heteroaryl is pyridyl or thienyl and aryl is optionally Substituted phenyl. Preferred substituents on the phenyl group based on alkyl, halogen, OH, alkoxy and -CF _3. Preferably, R ¹ is H, F, Br, pyridyl, OH-phenyl or -C≡C-CH ₂ OH. More preferably, R ¹ is H, F or Br.

In another embodiment of Formula I, R ^1A is H.

In another embodiment of Formula I, R ³ is selected from

a group of people.

In one embodiment of Formula I, the R ³ system or Preferably, the R ³ is a benzimidazolyl group, which is optionally substituted with one or two substituents independently selected from the group consisting of H, halogen, alkyl and alkoxy in the phenyl ring and R ⁶ in the imidazole moiety. Substituted by H or alkyl. Preferably, R ⁷ is selected from one of H, F, Br, Cl and -OCH ₃ substituents, or R ⁷ is independently selected from two substituents of Cl and F. R ^{6 is} preferably H, methyl or ethyl, more preferably H.

Formula I in another embodiment, R ⁴ Department of alkyl, cycloalkyl, halo, -CF ₃ or alkoxyalkyl embodiment. Preferably, R ⁴ is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, Br, -CF ₃ or methoxyethyl. When R ⁴ is a heteroaryl group, it is preferably a furyl group.

Formula I in another embodiment, R ⁵ is H or alkyl-based embodiment. Preferably, R ⁵ is H or ethyl.

In another embodiment of the compound of Formula I: -XY-system -C(R ⁴ )=N- or -N=C(R ⁴ )-; Z-system-(CH(R ² )) _n -(CH (R ^2A )) _m -; the sum of n and m is 1 to 3, preferably 2 to 3; R ² is H or methyl; R ^2A is H or methyl; R ¹ is H, halogen, pyridyl , optionally substituted phenyl or -C≡C-CH ₂ OH; R ^1A is H; R ³ Wherein R ⁷ is independently selected from 1 or 2 substituents of H, halogen, alkyl and alkoxy, and R ⁶ is H or alkyl; R ⁴ is alkyl, cycloalkyl, halogen, -CF ₃ Or alkoxyalkyl; and R ⁵ is H or alkyl.

In another embodiment of Formula I, -XY- is -C(R ⁴ )=N- or -N=C(R ⁴ )-; Z-system-(CH(R ² )) _n -(CH( R ^2A )) _m -; the sum of n and m is 1 to 3, preferably 2 to 3; R ² is H or methyl; R ^2A is H or methyl; R ¹ is H, F, Br, pyridine Base, OH-phenyl or -C≡C-CH ₂ OH; R ^1A is H; R ³ is Wherein R ⁷ is selected from a substituent consisting of H, F, Br, Cl and -OCH ₃ or R ⁷ is independently selected from two substituents of Cl and F, and wherein R ⁶ is H, methyl Or ethyl; R ⁴ is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, Br, -CF ₃ or methoxyethyl; and R ⁵ is H or Ethyl.

Preferred compounds of formula I are those of Examples 1A, 1B, 1E, 1I, 1O, 1P, 1Q, 1R, 1S, 1T, 1AA, 1BB, 1DD, 1FF, 1GG, 1HH, 1II, 1LL, 1MM, 1NN Compounds of 1 UU, 1XX, 1ZZ, 1BBB, 1DDD, 1FFF, 2B, 2D, 2F, 2G, 4A, 4D, 4E, 4F, 5B, 7A, 7D, 7E, 7K and 7O. More preferred compounds of formula I are those of the examples 1GB, 1M, 1N, 1O, 1P, 1Q, 1Z, 1EE, 1SS, 1VV, 2B, 2F, 4D and 7O.

In another embodiment of the invention, the compounds have the structural formula II.

In one embodiment of Formula II, p is 2 or 3.

In one embodiment of Formula II, R ¹¹ is H or alkyl. Preferably, R ¹¹ is H.

In another embodiment of Formula II, R ¹² is H or alkyl-based one embodiment. Preferably R ² is H or methyl, more preferably H.

In another embodiment of Formula II, the R ¹³ system Preferably, R ¹⁵ is independently selected from 1 or 2 substituents of H, halo, alkyl and alkoxy and R ¹⁴ is H or alkyl. Preferably, R ¹⁵ is H and R ¹⁴ is methyl.

In another embodiment of Formula II, R ¹⁶ and R ^{17 are} each H.

In another embodiment of Formula II, R ¹⁸ is alkyl or -CF ₃ . More preferably, R ¹⁸ is a tributyl group or -CF ₃ .

In another embodiment of Formula II, p is 2 or 3; R ¹¹ is H or alkyl, preferably H; R ¹² is H or alkyl, preferably H or methyl; and R ¹³ Wherein R ^{15 is} preferably one or two substituents independently selected from the group consisting of H, halogen, alkyl and alkoxy, more preferably H, and R ¹⁴ is H or alkyl, more preferably methyl; R ¹⁶ and R ^{17 is} each H; and R ¹⁸ alkyl or -CF ₃ , preferably t-butyl or -CF ₃ ; preferred compounds of formula II are the compounds of Examples 8, 8B and 8C.

As used herein, unless otherwise stated, the following terms are defined as follows: Mammals mean humans and other mammals.

Unless otherwise stated, the following definitions apply regardless of whether the term is used by itself or in combination with other terms. Therefore, the definition of "alkyl" can be applied to the "alkyl" portion of "alkyl" and "hydroxyalkyl", "haloalkyl", "alkoxy" and the like.

Alkyl means an aliphatic hydrocarbon group which may be straight or branched and which contains from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain from about 1 to about 6 carbon atoms in the chain. Branching means that one or more lower alkyl (e.g., methyl, ethyl or propyl) groups are attached to a linear alkyl group.

Hydroxyalkyl means an alkyl group as defined above substituted by 1 to 3 hydroxy groups. Bonding to the parent through the alkyl group.

Alkoxy means alkyl-O- wherein alkyl is as defined above. Non-limiting examples of suitable alkyl groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. Bonded to the parent moiety through ether oxygen.

The halogen atom means fluorine, chlorine, bromine and iodine.

The term "substituted" means that one or more hydrogen atoms of a given atom are replaced by a substituent selected from a specified group, the conditions of which cannot exceed the normal valence of the specified atom in the current environment, and the substitution is available. Stabilize the compound. Combinations of such substituents and/or symbols are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound which is sufficiently stable from the compound to withstand isolation from the reaction mixture and which is formulated as an effective therapeutic agent.

In the case of a compound, the term "isolated" or "in isolated form" refers to the physical state of the compound after separation from the synthetic or natural source or a combination thereof. In the case of a compound, the term "purified" or "in purified form" means that after the compound has been obtained from a purification process or as described herein or well known to those skilled in the art, it has sufficient to be described or skilled in the art. Well-known standard analytical techniques discriminate the purity of its features.

"Cycloalkyl" means a non-aromatic mono- or polycyclic ring system containing from about 3 to about 10 carbon atoms, preferably from about 3 to about 7 carbon atoms. A cycloalkyl group can be optionally substituted with one or more "ring system substituents" as defined herein, which may be the same or different. Non-limiting examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable polycyclic cycloalkyl groups include 1-naphthyl, borneol, adamantyl, and the like.

"Aryl" means an aromatic mono- or polycyclic ring system containing from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" as defined herein, which may be the same or different. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Heteroaryl" means a molecule comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms (wherein one or more ring atoms are other than carbon, such as nitrogen, oxygen or sulfur) Or more) aromatic monocyclic or polycyclic systems. Preferred heteroaryl groups contain from about 5 to about 6 ring atoms. "Heteroaryl" may be optionally substituted by one or more "ring system substituents" which may be the same or different as described herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least one nitrogen, oxygen or sulfur atom respectively is included as a ring atom. The nitrogen atom of the heteroaryl group can optionally be oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryl groups include pyridinyl, pyrazinyl, furyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isothiazolyl, cacao Azyl, thiazolyl, pyrazolyl, furazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, anthracene Zinyl, hydroxydecyl, imidazo[1,2-a]pyridyl, imidazo[2,1-b]thiazolyl, benzofurazinyl, fluorenyl, azaindole, benzo Imidazolyl, benzothienyl, quinolyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzazepine Mercapto, 1,2,4-triazinyl, benzothiazolyl, and the like. The term "heteroaryl" also refers to a partially saturated heteroaryl group such as, for example, tetrahydroisoquinolinyl, tetrahydroquinolyl and the like.

"Aralkyl" means an aryl-alkyl group wherein the aryl group and the alkyl group are as defined above. Preferred aralkyl groups comprise a lower alkyl number. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthylmethyl. Bonding to the parent moiety through the alkyl group.

"Heteroaralkyl" means a heteroaryl-alkyl group wherein heteroaryl and alkyl are as defined above. Preferred heteroaralkyl groups contain a lower alkyl number. Non-limiting examples of suitable heteroarylalkyl groups include pyridylmethyl and quinolin-3-ylmethyl. Bonding to the parent moiety through the alkyl group.

"Ring system substituent" means, for example, a substituent that is attached to an aromatic or non-aromatic ring system by replacing the available hydrogen on the ring system. The ring system substituents may be the same or different and each independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkaryl, heteroarylalkyl, heteroarylalkenyl, hetero Aralkynyl, alkaryl, -CH(Y ₁ )(Y ₂ ), -OY ₁ , hydroxyalkyl, alkoxyalkyl, alkoxyalkyl, haloalkoxy, -C(O) Y ₁ , halogen, nitro, cyano, -C(O) ₂ Y ₁ , -S(O) ₂ -Y ₁ , -SY ₁ , cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, Cycloalkenyl, -C(=N-CN)-NH ₂ , -C(=NH)-NH ₂ , -C(=NH)-NH(alkyl), -NY ₁ Y ₂ ,-alkyl-NY _a group consisting of ₁ Y ₂ , -C(O)NY ₁ Y ₂ and -SO ₂ NY ₁ Y ₂ , wherein Y ₁ , Y ₂ and Y ₃ may be the same or different and are independently selected from hydrogen, alkyl, aromatic a group consisting of a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, an aralkyl group, and a heteroaralkyl group. The "ring system substituents" on the aromatic ring may also be selected from -SF ₅ , -OSF ₅ , -Si(Y ₄ ) ₃ , -S(O)N(Y ₁ )(Y ₂ ), -C( =NOY ₁ )Y ₂ , -P(O)(OY ₁ )(OY ₂ ), -N(Y ₁ )C(O)Y ₂ , -CH ₂ -N(Y ₁ )C(O)Y ₂ , -CH ₂ -N(Y ₁ )C(O)N(Y ₁ )(Y ₃ ), -N(Y ₁ )S(O)Y ₂ , -N(Y ₁ )S(O) ₂ Y ₂ , -CH ₂ -N(Y ₁ )S(O) ₂ Y ₂ , -N(Y ₁ )S(O) ₂ N(Y ₂ )(Y ₃ ), -N(Y ₁ )S(O)N( Y ₂ )(Y ₃ ), -N(Y ₁ )C(O)N(Y ₂ )(Y ₃ ), -CH ₂ -N(Y ₁ )C(O)N(Y ₂ )(Y ₃ ) , -N(Y ₁ )C(O) ₂ (Y ₂ ), -CH ₂ -N(Y ₁ )C(O) ₂ (Y ₂ ), -S(O)Y _1, =NOY ₁ and -N _a group of ₃ , wherein Y ₁ , Y ₂ and Y ₃ are as defined above and each of Y _{4 is} independently selected from the group consisting of alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl and hetero Aralkyl. Further, the alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl portions of Y ₁ , Y ₂ and Y ₃ may optionally be selected independently from halogen, OH, -CF ₃ , CN, alkoxy. One or two substituents of the group consisting of -NH ₂ , -NH-alkyl, -N(alkyl) ₂ and Si(alkyl) _{3 are} substituted. "Ring system substituent" can also mean the simultaneous replacement of a single moiety of two available hydrogens (one H on each carbon) on two adjacent carbon atoms in the ring system. Examples of such moiety based methylenedioxy, ethylenedioxy-extending, -C (CH _{3) 2} - and the like, which will form the like such as, for example: and Part of the group.

Likewise, a single divalent moiety such as a divalent alkyl chain or a -O-(CH) ₂ -O- group can simultaneously replace two available hydrogen atoms on one carbon atom of the ring system. An example of one of these spiro ring groups is:

It should be noted that in the hetero atom-containing ring system of the present invention, there are no hydroxyl groups, halogens or amine groups on the carbon atoms adjacent to N, O or S, and no N or S groups on the carbon atoms to which another hetero atom is attached. So, for example, in the ring:

In the absence of -OH, a halogen atom or an amine group is directly bonded to the carbon atoms at positions 2 and 5.

When Z system Examples of such carbon rings versus

When Z system Examples of such heterocyclic rings versus

When -N(R ⁴ )- forms a 4 to 7 member ring with Z, examples of such rings are versus

It should be noted that any carbon atom and hetero atom system having a non-satisfied valence state in the text, reaction diagrams, examples, and tables herein assumes that there are sufficient numbers of hydrogen atoms to satisfy the equivalent state.

When a functional group in a compound is referred to as "protected", it means that the group is in a modified form, so that when the compound is reacted, undesired side reactions of the protected site are prevented. Suitable protecting groups are known to those skilled in the art and can be found in standard readings such as, for example, T. W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

When any code (e.g., alkyl, halogen atom, etc.) occurs more than once in any component or formula I or II, its definition at each occurrence is independent of the definition of each other occurrence.

As used herein, the term "composition" is intended to encompass a product comprising a specified quantity of the specified ingredient, and a product which is obtained directly or indirectly from a specified quantity of the specified ingredients.

Prodrugs, solvates and co-crystals of the compounds of the invention are also within the scope of this document. The discussion of prodrugs is based on T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the ACS Symposium Series and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Available in the Association and Pergamon Press. The term "prodrug" means a compound that is converted in vivo to produce a compound of formula I or a pharmaceutically acceptable salt, hydrate or solvate of the compound (eg, a prodrug). This transformation can occur by various mechanisms (e.g., metabolic or chemical processes), such as, for example, hydrolysis in blood. Discussion of the use of prodrugs by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems", ACS Symposium Series, column 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, available in 1987.

For example, if the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, the prodrug may comprise a hydrogen atom of the acid group substituted with the following group. An ester such as, for example, (C ₁ -C ₈ )alkyl, (C ₂ -C ₁₂ )alkylnonyloxymethyl, 1-(alkyloxy)ethyl having 4 to 9 carbon atoms, 1-methyl-1-(alkyloxy)-ethyl having 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, having 1 to 7 carbon atoms -(alkoxycarbonyloxy)ethyl, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl) having 3 to 9 carbon atoms Aminomethyl, 1-(N-(alkoxycarbonyl)amino)ethyl, 4-mercapto, 4-crotonolide, γ-butyrolactone-4-, 4 to 10 carbon atoms , bis-N,N-(C ₁ -C ₂ )alkylamino (C ₂ -C ₃ )alkyl (such as β-dimethylaminoethyl), amine mercapto-(C ₁ -C ₂ An alkyl, N,N-di(C ₁ -C ₂ )alkylaminemethanyl-(C ₁ -C ₂ )alkyl group and piperidinyl-, pyrrolidinyl- or morpholino (C ₂ - C ₃ ) an alkyl group or the like.

Similarly, if the compound of formula (I) contains an alcohol functional group, the prodrug can be formed by substituting a hydrogen atom on the alcohol group for a group such as, for example, a (C ₁ -C ₆ ) alkano group. Oxymethyl, 1-((C ₁ -C ₆ ) alkoxy)ethyl, 1-methyl-1-((C ₁ -C ₆ ) alkoxy)ethyl, (C ₁ - C ₆ ) alkoxycarbonyloxymethyl, N-(C ₁ -C ₆ ) alkoxycarbonyloxyamine methyl, amber fluorenyl, (C ₁ -C ₆ )alkyl fluorenyl, α-amino group (C ₁ -C ₄ )alkyl, arylsulfonyl and α-amine fluorenyl, or α-aminoindolyl-α-amine fluorenyl (wherein each α-amine fluorenyl group is independently selected from naturally occurring L-amino groups Acid), P(O)(OH) ₂ , -P(O)(O(C ₁ -C ₆ )alkyl) ₂ or a glycosyl group (obtained by removing the hydroxyl group of the carbohydrate in the form of a hemiacetal) Free radical) and the like.

If the compound of formula (I) contains an amino functional group, the prodrug may be formed by displacement of a hydrogen atom in the amine group to a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl (wherein R and R' are each independently (C ₁ -C ₁₀ )alkyl, (C ₃ -C ₇ )cycloalkyl, benzyl, or R-carbonyl natural alpha-amine sulfhydryl or natural alpha-amine fluorenyl ), -C(OH)C(O)OY ^1A (where Y ^1A is H, (C ₁ -C ₆ )alkyl or benzyl); -C(OY ^2A )Y ^3A (wherein Y ^2A (C) ₁ -C ₄ )alkyl and Y ^3A is (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl,amino(C ₁ -C ₄ )alkyl or mono-N- or di -N,N-(C ₁ -C ₆ )alkylaminealkyl); -C(Y ^4A )Y ^5A (wherein Y ^4A is H or methyl and Y ^5A is mono-N- or di-N,N -(C ₁ -C ₆ )alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl) and the like.

"Solvate" means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. The solvate may be isolated in some instances, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both the solution phase and the solvate. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. The "hydrate" is a solvate in which the solvent molecule is H ₂ O.

One or more compounds of the invention may optionally be converted to a solvate. The preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3) , 601-611 (2004) are described in ethyl acetate ethyl and using water to prepare an antifungal fluconozole solvate. . Similar preparations of solvates, hemisolvates, hydrates, and the like are described in EC van Tonder et al., AAPS Pharm Sci Tech., 5(1) , Paper 12 (2004); and AL Bingham et al., Chem. Commun. , 603-604 (2001). A typical non-limiting process involves dissolving a compound of the invention in a desired amount of the desired solvent (organic or water or a combination thereof) at a temperature above ambient and cooling the solution at a rate sufficient to form crystals. The crystals are then separated by standard methods. Analytical techniques such as, for example, IR spectroscopy, show that the solvent (or water) in crystalline form is present as a solvate (hydrate).

Co-crystal refers to a crystalline superstructure formed by the combination of an active pharmaceutical intermediate with an inert molecule that provides crystallinity to the bound form. Co-crystallization is usually obtained by reacting a dicarboxylic acid such as fumaric acid, succinic acid or the like with a basic amine such as represented by the compound I or II of the present invention in various proportions depending on the properties of the co-crystal. (Rmenar, JF et al., J Am. Chem. Soc. 2003 , 125, 8456).

An "effective amount" or "medical effective amount" is intended to describe an amount of a compound or composition of the invention that is effective as a PDE10 inhibitor, thereby producing the desired therapeutic, ameliorating, inhibiting or preventing effect.

The compounds of formula I and II can form salts which are also within the scope of the invention. Unless otherwise stated, reference to a compound of Formula I or II herein is to be understood to include reference to its salt. As used herein, the term "salt" refers to an acid salt formed with an inorganic and/or organic acid, and a basic salt formed with an inorganic and/or organic base. Further, when the compound of Formula I or II contains both a basic group such as, but not limited to, pyridine or imidazole, and an acidic group such as, but not limited to, a carboxylic acid, a zwitterion ("internal salt") may be formed and It is included in the term "salt" as used herein. While pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, other salts may also be employed. A salt of a compound of formula I can be reacted, for example, by reacting a compound of formula I or II with an amount, such as an equivalent amount of an acid or a base, in a medium such as a salt which can precipitate the salt, or in an aqueous medium, followed by lyophilization. form.

Exemplary acid addition salts include acetate, ascorbate, benzoate, besylate, hydrogen sulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumaric acid Salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, water Salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and the like. Further, an acid system which is generally considered to be suitable for forming a pharmaceutically acceptable salt with an alkaline pharmaceutical compound is disclosed, for example, in P. Stahl et al., Camille G. (ed) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich : Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC). These documents are incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic bases such as dicyclohexylamine, and third butylamine (eg, organic a salt of an amine, and a salt containing an amino acid such as arginine, lysine or the like. The basic nitrogen-containing group may be represented by, for example, a lower alkyl number halide (eg, methyl, ethyl, and butyl chloride, bromide, and iodide), a dialkyl sulfate (eg, dimethyl Base, diethyl and dibutyl sulfate), long chain halides (eg, sulfhydryl, lauryl and stearyl chloride, bromide and iodide), aralkyl halides (eg, benzyl and Benzyl bromide, and the like are quaternized.

All such acid salts and base salts are pharmaceutically acceptable salts within the scope of the invention, and for the purposes of the present invention, all acid and base salts and the free forms of the corresponding compounds are considered equivalent.

The compounds of the invention may form esters which are also within the scope of the invention.

The pharmaceutically acceptable ester of the compound of the present invention includes the following groups: (1) a carboxylate obtained by esterifying a hydroxyl group, wherein the non-carbonyl moiety of the carboxylic acid moiety of the ester group is selected from a linear or branched chain. Alkyl (for example, ethyl, n-propyl, tert-butyl or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (eg, phenoxymethyl), aryl (eg, phenyl substituted, for example, halo, C _1-4 alkyl C _1-4 alkoxy or amine); (2) sulfonate a group such as an alkyl- or aralkylsulfonyl group (for example, a methylsulfonyl group); (3) an amino acid ester group (for example, an L-guanidinium group or an L-isoleucine group); 4) Phosphonates and (5) mono-, di- or triphosphates. The phosphates can be further esterified, for example, with a C _1-20 alcohol or a reactive derivative thereof, or with 2,3-di(C _6-24 )mercaptoglycerol.

The compounds of formulas I and II, and salts, solvates, esters, co-crystals and prodrugs thereof, may exist in their tautomeric form (for example, a guanamine or an imine ether). All such tautomeric forms are incorporated herein as part of the present invention.

The compounds of formula (I) and (II) may contain asymmetric or palmitic centers and, therefore, may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of formula (I) and (II), as well as mixtures thereof (including racemic mixtures), form part of the present invention. Furthermore, the invention encompasses all geometric and positional isomers. For example, if a compound of formula (I) or (II) is incorporated into a double bond or a fused ring, both cis- and trans forms, as well as mixtures, are included within the scope of the invention.

Diastereomeric mixtures can be separated by their physicochemical differences by methods known to those skilled in the art, for example, by chromatography and/or fractional crystallization to separate their respective diastereomeric Structure. Separation of enantiomers by conversion of an enantiomeric mixture with a suitable optically active compound (for example, a palmitic adjuvant such as palmitol or Mosher's mercapto chloride) to a diastereomeric mixture The diastereomers are separated and the respective diastereomers are converted (eg, hydrolyzed) to the corresponding pure enantiomers. Furthermore, certain compounds of formula (I) and (II) may be atropisomers (e.g., substituted biaryl compounds) and are considered as part of this invention. Enantiomers can also be separated using a palm HPLC column.

The compounds of formula (I) and (II) may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Further, for example, the keto-enol and imine-enamine forms of the compounds are included in the present invention.

All stereoisomers of the compounds of the invention (including salts, solvates, esters, co-crystals and prodrugs of such compounds, and salts and solvates and esters and co-crystals of such prodrugs) (eg, geometry) Isomers, optical isomers, etc., such as those that occur due to asymmetric carbons on various substituents (including enantiomeric forms (which may even exist without asymmetric carbon)), Rotose isomeric forms, atropisomers and diastereomeric forms), as well as positional isomers (e.g., 4-pyridyl and 3-pyridyl) are embraced within the scope of the invention. The respective stereoisomers of the compounds of the invention, for example, are substantially free of other isomers, or may be, for example, a mixture of rotamers or mixed with all other or other selected stereoisomers. The palm center of the present invention may have an S or R configuration as defined by the IUPAC 1974 standard. The terms "salt", "solvate", "ester", "prodrug" and the like are equally applicable to the enantiomers, stereoisomers, rotamerization, tautomers, positions of the compounds of the invention. Salts, solvates, esters and prodrugs of isomers, racemates or prodrugs. The isomers can be obtained by reacting a purely optically or enriched optical starting material or by isolating the isomer of the compound of formula I or II using conventional techniques. Isomers may also include geometric isomers, for example, when a double bond is present.

Those skilled in the art will appreciate that among certain compounds of formula I and II, one of the isomers may exhibit higher pharmacological activity than the other isomers.

The polymorphs of the salts of the compounds of the formulae I and II and the salts, solvates, esters, co-crystals and prodrugs of the compounds of the formulae I and II are included in the invention.

In the present specification, the term "at least one compound of formula I (or II)" means one or three different compounds of formula I or II which are useful in pharmaceutical compositions or methods of treatment. Preferably, a compound of formula I or II is used.

The present invention also encompasses the labeled isotopic compounds of the present invention, except that one or more of the atomic systems are replaced by atoms having an atomic mass or mass number different from the mass or mass number generally found in nature. The compounds cited are the same. Examples of isotopes which may be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and isotopes of chlorine and iodine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl and ¹²³ I.

Certain labeled isotope compounds of formula (I) (e.g., such compounds labeled with ³ H and ¹⁴ C) can be used in compound and/or substrate distribution assays. The ruthenium (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotope systems are particularly suitable for their convenient preparation and detection. Certain labeled isotope compounds of formula (I) are useful for medical imaging purposes. For example, they may be used for positron emission tomography (PET) applications, such as ¹¹ C or ¹⁸ F compounds, and their compounds that emit gamma-ray isotopes (such as ¹²³ I) may be used. The use of photon emission computed tomography (SPECT). In addition, substitution by heavier isotopes such as deuterium (ie, ² H) may provide a medical advantage due to greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), which may be appropriate for a certain Some environments. In addition, isotope substitution at the position where epimerization occurs will slow or reduce the epimerization process and thereby maintain a higher activity or effective form of the compound for a longer period of time. Compounds of formula (I) labeled with isotopes, especially those containing longer half-life (T1/2 > 1 day) isotopes, can generally be modified analogously to the processes disclosed in the reaction schemes and/or examples below. Prepare by substituting an unlabeled isotope reagent with a suitable labeled isotope reagent.

The invention further encompasses compounds of formulas I and II in all isolated forms. The compounds of formula I and II are prepared by methods known in the art. A typical preparation of a compound of Formula I is shown in Reaction Scheme 1, wherein -XY- based -C (R ⁴⁾ = N-, and the sum of n and m is 2 or 3.

The compound of formula I wherein -XY-line-N=C(R ⁴ )- is prepared by the same method (see Example 2 below).

Wherein -XY- based ^{-C (R 4) = C (} R 4) - of the Formula I compound is prepared by the methods known in the present art.

Compounds of formula II are prepared by methods known in the art. A typical process line for the preparation of compounds of formula II is shown in Example 8.

In the above reaction scheme and the following preparation examples, the following abbreviations are used: RT-room temperature; Ac-acetamido; Me-methyl; Et-ethyl; Ph-phenyl; i-Pr-isopropyl; t-Bu - tert-butyl; t-Boc-N-tris-butoxycarbonyl; BINAP-2,2'-bis(diphenylphosphino)-1,1'binaphthyl; m-CPBA-m-chloroperoxy Benzoic acid; BUN-1,8-diazobicyclo[5.4.0]undec-7-ene; DMF-dimethylformamide; EDC-1-(3-dimethylaminopropyl) 3-ethylcarbodiimide; HOBT-1-hydroxybenzotriazole hydrate; THF-tetrahydrofuran; TFA-trifluoroacetic acid; TLC-thin chromatography; DIPEA-diisopropylethylamine; KHMDS - Bis(trimethyldecyl) potassium amination.

When LC/MS data was presented, it was analyzed using an Applied Biosystems API-150 mass spectrometer and a Shimadzu SCL-10A LC system. Column: Phenomenex Gemini C18, 5 μm, 50 mm × 4.6 mm ID; Gradient: from 90% water, 10% CH ₃ CN and 0.05% TFA, 5 minutes, 5 minutes to 5% water, 95% CH ₃ CN , 0.05% TFA. MS data was obtained using an Agilent Technologies LC/MSD SL or a 1100 Series LC/MSD mass spectrometer. Unless uv is noted, the residence time is the total ion current (TIC).

The following are examples of the preparation of intermediates and compounds of formulas I and II.

Reaction of [1,2,4]triazolopyridine-8-carboxylic acid 5 in Figure 1 for the synthesis of 3-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine Process synthesis of -8-formic acid 12 :

step 1:

A mixture of ethyl 2-chloronicotinate 8 (2.0 g) and hydrazine (0.4 ml) was heated to 60 ° C for 4 hours in dioxane (50 ml). The mixture was cooled to RT and concentrated to give a yellow solid (2.8 g) in vacuo and purified by the system based on silicon oxide as a yellow solid (eluted by CH ₂ Cl ₂₎ the column chromatography, a yellow solid 9 (0.75 g). LCMS: M+1 was 182 at 1.37 and 0.8 minutes.

Step 2:

9 (0.75 g), cyclopropylformic acid (0.35 g), EDC‧HCl (0.94 g), N-methylmorpholine (0.53 ml) and HOBT (10 mg) in CH ₂ Cl ₂ (20 ml) The mixture was stirred at RT for 16 hours. The mixture was diluted with CH ₂ Cl ₂ and extracted with H ₂ O (3×30 mL). The organic layer was dried by lines MgSO _4, filtered and concentrated in vacuo to give a yellow solid of 10 (1.0 g), as a yellow solid which was used without further purification system used in the next step. LCMS: M+1 was 1.70 and 250 at 0.82 minutes.

Preparation of 10-1:

With an addition funnel, over 30 minutes to trifluoroacetic anhydride was added dropwise to 9 (10.0 g) and Et ₃ N (11.2 g) in dry CH ₂ Cl ₂ (60 ml) cooled (0 deg.] C) stirred mixture of . After the addition was complete, the ice bath was removed and the mixture was stirred for 3 hours at RT, then by H ₂ O (200 ml) to suspend the reaction. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3×100 ml). The organic layer was dried by a combination of lines MgSO _4, filtered, and concentrated in vacuo to give 10-1 of organic solids, organic solids used without further purification in the next step. LCMS: M+1 was 278.2 at 3.1 minutes.

Step 3:

POCl ₃ (1 ml) was added to a stirred solution of 10 (0.76 g) in hexanes (15 ml). The mixture was cooled to RT and concentrated in vacuo to give a residue. The residue was dissolved in EtOAc and washed by a saturated aqueous solution of NaHCO _3. The organic layer was dried by lines MgSO _4, filtered and concentrated in vacuo to give a brown solid of 11 (0.37 g). LCMS: M+1 was 232 at 1.56, 12.8, and 0.88 minutes.

Step 4:

NaOH (1 ml of a 2.5 N aqueous solution) was added to a cooled (0 ° C) stirred solution of the ester 11 (0.36 g) of EtOH (7 ml), and the mixture was slowly warmed to RT for 3 hours. The reaction was quenched by the addition of cone. HCl to pH 2 to 3 and concentrated in vacuo to afford a solid. Water was added and the solid was filtered to give acid 12 (0.17 g) as a white solid.

The following compounds were prepared in the same manner.

The reaction of (benzimidazol-2-yl)ethylamine 6 in Figure 1 is commercially available or according to the synthesis of 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl) Process synthesis as disclosed in amine 16 .

step 1:

N-methylmorpholine (1 ml) was added to a stirred solution of β-N-Boc-alanine (1.81 g) in DMF (10 ml) cooled (-20 ° C). The mixture was stirred at -20 ° C for 10 minutes, followed by the addition of isobutyl chloroformate (1.2 ml). After stirring for an additional 10 minutes, 4,5-dichlorophenylenediamine ( 13 ) (1.70 g) was added to the reaction mixture. The resulting mixture was slowly warmed to RT for 1 hour and stirred for 18 hours. The reaction mixture was concentrated in vacuo and redissolved in EtOAc. The organic layer was washed sequentially with H ₂ O, aq. NaHCO ₃ and then brine. The organic layer was dried by line MgSO _4, filtered and concentrated in vacuo to give 14 (2.73 g) of a dark brown foam. LCMS: M+1 was 348 at 3.75 minutes.

Step 2:

A mixture of compound 14 (2.72 g) and glacial acetic acid (10 ml) was heated to 65 °C for 3 h. The mixture was cooled to EtOAc EtOAc (EtOAc m. Obtain 15 (1.10 g). LCMS: M+1 was 330 at 2.61 minutes.

Step 3:

The (1 ml) was added TFA to CH containing compound 15 (0.51 g) of (1 ml) was stirred ₂ Cl ₂ solution, and the mixture was stirred at RT 1 h. The reaction mixture was concentrated in vacuo to give an oil (0.45 g), the oil was redissolved in CH ₂ Cl _2. Then with saturated aqueous K ₂ CO ₃ The organic layer was washed, dried by MgSO _4, filtered and concentrated in vacuo to give a yellow solid of 16 (0.22 g). LCMS: M+1 was 230 at 2.08, 1.57, and 1.03 minutes.

The following compounds were prepared in the same manner.

Example 1

A mixture of acid 12 (150 mg), amine 16 (210 mg), EDC HCl (150 mg) and HOBT (120 mg) in DMF (8 ml) was stirred at RT for 16 h. The reaction was quenched by H ₂ O and extracted with CH ₂ Cl ₂ (3×20 ml). The organic layer was then dried by lines MgSO _4, filtered and concentrated in vacuo to obtain a residue, the residue was subjected to preparative TLC over silica gel (in _{19: 1 CH 2 Cl 2:} MeOH elution) to afford an off-white solid Example 1 (105 mg). LCMS: M+1 was 415 at 2.46 minutes.

The following compounds were prepared in the same manner.

Example 2

Add DIPEA (0.23 g) dropwise to 2-(5-chloro-1H-benzimidazol-2-yl)-ethylamine dihydrate in cooled (0 ° C) stirred CH ₂ Cl ₂ (7 mL) Acid salt ( 16-3 ) (0.49 g) solution. After stirring at 0 ° C for 20 minutes, Me ₃ Al (1.0 ml of a 2.0 M solution in toluene) was added. The mixture was stirred at RT for 1 hour, and when a full amount of ester 17 (100 mg) was added in one portion, it was cooled back to 0 °C. The mixture was stirred at RT overnight and then cooled to 0 °C. The reaction by a saturated aqueous solution of Na-K- tartrate salt quenched and diluted by H ₂ O. The resulting solution was extracted by CH ₂ Cl ₂ (3×20 ml). The organic layer was dried by a combination of lines MgSO _4, filtered and concentrated in vacuo to obtain a residue, which was based the residue by silica gel column chromatography (0 to 8% MeOH by the CH ₂ Cl ₂ solution was washed Purification afforded 1Z (28 mg) and Example 2 (7 mg).

Using the same process, the following compounds were prepared:

Example 3

It will contain 1E (50 mg), amine (19.5 mg), DBU (11.6 mg), Mo(CO) ₆ (15 mg), t-Bu ₃ PHBF ₄ (1 mg) and [2-(di-) A mixture of O-tolyl-phosphino)benzyl]dipalladium(II) (1.2 mg) in THF (1 ml) was then warmed to &lt The reaction mixture was concentrated in vacuo to obtain a residue, the residue was purified by preparative TLC (in a _{5: 1 CH 2 Cl 2:} MeOH elution) was obtained as an off-white solid of Example 3 (12.2 mg). LCMS: M+1 was 504 at 2.44 minutes.

The following compounds were prepared by the same process using the appropriate amine:

Example 4

1E (60 mg), 4-(trifluoromethyl)phenyldihydroxyboronic acid (77.5 mg), Pd(PPh ₃ ) contained in MeCN (1 ml) and H ₂ O (0.25 ml) under microwave A mixture of ₄ (15.7 mg) and Na ₂ CO ₃ (72 mg) was heated to 140 ° C for 15 minutes. The mixture was poured into the column, and by silica gel column chromatography _{(30: 1 CH 2 Cl 2:} MeOH elution) to give a yellow solid of Example 4 (44.9 mg). LCMS: M+1 was 507 at 3.26 minutes.

Using the same process, the following compounds were prepared:

Example 5

Add 4-ethynylanisole (36 mg) to 1E (60 mg), Pd(PPh ₃ ) ₂ Cl ₂ (4.8 mg), Cul (1.3 mg) and Et ₃ N in THF (1 ml). (206 mg) in a stirred mixture. The mixture was stirred at RT for 3 days. The reaction system was quenched by H ₂ O and (3 × 10 ml) and extracted with CH ₂ Cl _2. The organic layer was dried by the compositions based MgSO _4, filtered and concentrated in vacuo to obtain a residue, the residue was purified by silica gel column chromatography (20: MeOH elution: 1 CH ₂ Cl ₂₎ to afford Example 5 of yellow solid (37 mg). LCMS: M+1 was 493 at 3.21.

Using the same process, the following compounds were prepared:

Example 6

10% Pd/C (20 mg) was added to Example 5 (32 mg) in EtOH (3 ml). The mixture was filtered and the filtrate was concentrated to obtain a residue, the residue (in _{20: 1 CH 2 Cl 2:} MeOH elution) was purified by silica gel column chromatography to give a pale yellow solid of Example 6 (20 mg). LCMS: M+1 was 497 at 2.91 minutes.

The following compounds were prepared in the same manner.

Examples 7 and 7A

KHMDS (0.55 ml of a 0.5 M solution in toluene) was added to a cooled (-78 ° C) stirred solution containing 1P (104 mg) anhydrous THF (8 ml). After stirring at -78 ° C for 30 minutes, Mel (0.019 ml) was added dropwise. The cold bath was removed and the mixture was warmed to RT and stirred overnight. The reaction system by the reaction was quenched with saturated aqueous NaHCO _3, and extracted by EtOAc, dried by MgSO _4, and filtered. The filtrate was concentrated in vacuo to obtain a residue, the residue was purified by silica gel column chromatography (0 to 20% acetone in CH ₂ Cl ₂ elution) to afford 7 (41 mg) and Example Example 7A (32 mg ). LCMS: M+1 was 395 (Example 7) at 2.14 minutes and 395 (Example 7A) at 2.10 minutes.

Using the same process, the following compounds were prepared:

Example 8

step 1:

A total amount added mCPBA (5.54 g, 77%) to a solution cooled (0 deg.] C) of 18 (3.34 g) of CHCl ₃ (35 ml) at room temperature. The cold bath was removed and the mixture was stirred at RT 3 h, then by saturated Na ₂ CO ₃ solution quenched. The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2×30 ml). The organic layer was dried by the compositions based MgSO _4, filtered and concentrated in vacuo to give N- oxide 19, which was used without further purification was used directly in the next step.

Step 2:

The N- oxide of POCl 19 ₃ (35 ml) was heated to 105 ℃ overnight and then heated at 120 ℃ 20 hours. The mixture was cooled to RT, poured into ice water, and by NH ₄ OH solution. The resulting solution was extracted by CH ₂ Cl ₂ (3×30 ml). Dried MgSO _4, filtered and concentrated in vacuo to obtain a residue by silica gel column chromatography of the residue-based composition of the organic layer by line (10: 1 hexanes: ethyl acetate) gave Obtained 20 (1.3 g) of light brown solid. LCMS: M+2 was 244 at 4.45 minutes.

Step 3:

NH ₂ NH ₂ (0.1 ml) was added to a stirred solution of 20 (0.5 g) of 1,4-dioxane (20 ml), and the mixture was heated to 64 ° C overnight. An additional 0.1 ml of NH ₂ NH _{2 was added} and stirring was continued for an additional 5 hours at 64 °C. The solvent was evaporated in vacuo and the residue was taken directly to next next

Et ₃ N (0.42 g) was added to a cooled (0 ° C) stirred solution containing anhydrous CH ₂ Cl ₂ (6 ml) from the above product, followed by dropwise addition of trifluoromethane via a syringe over 5 minutes. Acetic anhydride (0.56 g). After stirring at 0 ° C for 1 hour and at RT for an additional 1 hour, the reaction was quenched by H ₂ O (20 mL). The organic layer was separated and the aqueous layer was extracted with CH ₂ Cl ₂ (3×20 ml). Dried MgSO _4, filtered and concentrated in vacuo to obtain a solid which was used directly in the system the next step without further purification by the combined organic layers.

POCl ₃ (0.5 ml) was added to a stirred solution of 1,2-dichloroethane (5 ml) from the intermediate obtained above, and the mixture was heated at 84 ° C overnight. The mixture was cooled to RT, poured into ice water, and the solution was carefully ₄ OH NH by neutralization. The resulting solution was extracted by CH ₂ Cl ₂ (3×20 ml). The organic layer was dried by a combination of lines MgSO _4, filtered and concentrated in vacuo to obtain a residue, which was based the residue by silica gel column chromatography (50: MeOH elution: 1 CH ₂ Cl ₂₎ Purification, Obtained 22 (0.31 g) as a pale yellow solid. LCMS: M was 316 at 4.05 min.

The following compounds were prepared in the same manner.

Step 4:

In a sealed tube, bromide 22 (60 mg), amine 23 (60 mg), ginseng (dibenzylideneacetone)-dipalladium (0) (8.7 mg), BINAP (containing toluene (1.5 ml)) A mixture of 3.5 mg) and sodium butoxide (55 mg) was heated to 115 ° C for 24 hours. The reaction was cooled to RT and concentrated in vacuo to obtain a residue, which was based the residue (in _{20: 1 CH 2 Cl 2:} MeOH elution) over silica gel was purified by preparative TLC, was obtained as a solid of Example 8. LCMS: M+1 was 411 at 3.27 minutes.

The following compounds were prepared in the same manner.

The amount and frequency of administration of the active compound and/or its pharmaceutically acceptable salt employed will be adjusted according to the adjustments made by the attending physician after considering the age, condition and weight of the patient. A typical recommended dosage regimen can range from about 10 mg/dose to about 100 mg/dose, preferably from about 10 to about 50 mg/dose, and more preferably from about 20 to about 25 mg/dose.

When a pharmaceutical composition is prepared from a compound of the present invention, the inert, pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, lozenges, dispersible granules, capsules, film ingots, and suppositories. The powders and lozenges may contain from about 5 to about 95% active ingredient. Suitable solid carriers known in the art are, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, film-coated tablets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of making the various compositions can be found in A. Gennaro (ed.), The Science and Practice of Pharmacy, 20th Edition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

Liquid form preparations include solutions, suspensions and emulsions. Examples which may be mentioned are water or water-propylene glycol solutions for intravenous injection, or sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for nasal administration.

Aerosol formulations suitable for inhalation may include solutions and solids in powder form, which may be combined with apharmaceutically acceptable carrier such as an inert compressed gas such as nitrogen.

Solid form preparations may also be included which are intended to be converted, before use, into liquid form preparations for oral or intravenous administration. This liquid form preparation includes solutions, suspensions and emulsions.

The compounds of the invention may also be administered transdermally. The dermally administrable composition can be in the form of a cream, lotion, aerosol, and/or lotion and can be included in a matrix or liquid-storage skin patch for this purpose as is conventional in the art.

Preferably, the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation is subdivided into suitable unit dosage forms containing appropriate quantities, such as an effective amount of the active ingredient for the desired purpose.

The actual dosage employed can vary depending on the needs of the patient and the severity of the condition to be treated. The establishment of an appropriate dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dose can be divided and administered in divided doses as needed.

The amount and frequency of administration of the compounds of the invention and/or their pharmaceutically acceptable salts are adjusted according to the attending physician's consideration, such as the age, condition and size of the patient, and the severity of the condition to be treated. A typical recommended daily dose for oral administration may range from about 1 mg/day to about 300 mg/day, preferably from 1 mg/day to about 75 mg/day, and is administered in two to four doses. .

The activity of the compounds of formula I and II can be determined by the following procedure.

In vitro PDE10 assay

PDE10A1 activity was determined in a white opaque 384-well Opti-Plates assay plate (Perkin Elmer Life Sciences) using scintillation approximation analysis (GE Healthcare). Human recombinant PDE10A1 was purchased from BPS Bioscience, Inc. The reaction mixture contains PDE10A1 (0.02 nM), 10 nM [ ³ H]cAMP ([5',8- ³ H]adenosine 3', 5'-cyclic phosphate, ammonium salt, Amersham) and various concentrations of compounds, including 50 mM Tris-HCl, pH 7.5; 8.3 mM MgCl ₂ ; 17 mM EGTA and 0.2% bovine serum albumin in a total volume of 30 μl. The assay was started with the addition of the substrate and allowed to proceed for 30 minutes at room temperature, then the reaction was stopped by the addition of 300 μg of 钇SPA PDE beads. The reaction mixture was thoroughly mixed and the beads were allowed to stand for 30 minutes. The panels are then counted in a TopCount scintillation counter. Under these conditions, the hydrolyzed substrate is less than 30% in the absence of the compound. Ki values were determined as described by Cheng and Prusoff (1973).

Using the above test method, it was found that the following compounds of formula I have Ki values of less than 50 nM: Examples 1A, 1B, 1E, 1I, 1O, 1P, 1Q, 1R, 1S, 1T, 1AA, 1BB, 1DD, 1FF, 1GG, 1HH 1II, 1LL, 1MM, 1NN, 1UU, 1XX, 1ZZ, 1BBB, 1DDD, 1FFF, 2B, 2D, 2F, 2G, 4A, 4D, 4E, 4F, 5B, 7A, 7D, 7E, 7K and 7O. The following compounds of formula I were found to have Ki values of less than 10 nM: Examples 1 GB, 1 M, 1 N, 1 O, 1 P, 1 Q, 1 Z, 1 EE, 1 SS, 1 VV, 2B, 2F, 4D and 7O.

Using the test methods described above, it was found that the following compounds of formula II have Ki values of less than 50 nM: Examples 8, 8B and 8C.

Although the present invention has been described in connection with the specific embodiments described above, those skilled in the art can understand many alternatives, modifications, and other changes. All such substitutions, modifications and variations are within the spirit and scope of the invention.

Claims (12)

a compound of formula I, Or a pharmaceutically acceptable salt thereof, wherein -XY- is -N=C(R ⁴ )- or -C(R ⁴ )=N-; R ¹ is H, halo, C _1-6 alkyl, C _{1- 6} alkoxy, -CF ₃ , C _1-6 alkoxy-C _1-6 alkoxy, OH, hydroxy C _1-6 alkyl, -OCF ₃ , benzyloxy, -C(O)OC _{1- 6} alkyl, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -C _1-6 alkyl N(R ⁶ ) ₂ , CN, -SR ⁶ , aryl, -C≡ C-CH ₂ OH, -C≡C-aryl, aryl C _1-6 alkyl-, -C(O)NHCH _2- aryl, heteroaryl, -C≡C-heteroaryl, heteroaryl C _1-6 alkyl, -C(O)NHCH ₂ -heteroaryl, , or ; R ^1A is H, halo, C _1-6 alkyl, C _1-6 alkoxy, -CF ₃ , C _1-6 alkoxy-C _1-6 alkoxy, OH, hydroxy C _1-6 Alkyl, -OCF ₃ , -C(O)OC _1-6 alkyl, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -C _1-6 alkyl N (R ⁶ ₂ , CN, -SR ⁶ , -C≡C-CH ₂ OH, -C≡C-aryl or aryl C _1-6 alkyl-; Q-system -O-, -N(R ¹⁰ )-,- S-, -SO-, -SO ₂ - or -CH ₂ -; Z-system-(CH(R ² )) _n -(CH(R ^2A )) _m -; n system 1 or 2; m system 0, 1 Or 2; each R ² is independently selected from the group consisting of H and C _1-6 alkyl; each R ^2A is independently selected from H, C _1-6 alkyl, fluoro, OH, C _1-6 alkoxy a group consisting of -N(R ⁸ ) ₂ or -C _1-6 alkyl-N(R ⁸ ) ₂ ; R ³ is selected from the group consisting of pyridine, pyrazine, , versus a group consisting of; each R ⁴ is independently selected from the group consisting of H, C _1-6 alkyl, C _3-10 cycloalkyl, halo, -CF ₃ , C _1-6 alkoxy-C _1-6 alkyl, a group consisting of heteroaryl, -CN, hydroxy C _1-6 alkyl, aryl, aryl C _1-6 alkyl-, heteroaryl C _1-6 alkyl, -OCF ₃ and -N(R ⁶ ) ₂ R ⁵ is H or C _1-6 alkyl; each R ⁶ is independently selected from the group consisting of H and C _1-6 alkyl; R ⁷ is independently selected from H, halo, C _1-6 alkane , C _1-6 alkoxy, -CF ₃ , C _3-10 cycloalkyl, C _1-6 alkoxy-C _1-6 alkoxy, OH, hydroxy C _1-6 alkyl, -OCF ₃ , -C(O)OC _1-6 alkyl, -C(O)N(R ⁶ ) ₂ , -N(R ⁶ ) ₂ , -C _1-6 alkyl N(R ⁶ ) ₂ , CN, - 1 or 2 substituents of the group consisting of SR ⁶ and trimethyldecane; each R ⁸ is independently selected from the group consisting of H and C _1-6 alkyl; R ⁹ is independently selected from H and C ₁ 1 to 3 substituents of the group of _-6 alkyl groups, and when Q is -CH ₂ -, R ⁹ may be halo, OH, C _1-6 alkoxy or -CF ₃ ; and R ¹⁰ H or C _1-6 alkyl. The compound of claim 1, wherein: -XY-system -C(R ⁴ )=N- or -N=C(R ⁴ )-; Z-system-(CH(R ² )) _n -(CH(R ^2A )) _m -; the sum of n and m is 1 to 3; R ² is H or C _1-6 alkyl; R ^2A is H or C _1-6 alkyl; R ¹ is H, halo, pyridyl, Phenyl or -C≡C-CH ₂ OH unsubstituted or substituted with C _1-6 alkyl, halogen, OH, C _1-6 alkoxy or -CF ₃ ; R ³ or Wherein R ⁷ is independently selected from 1 or 2 substituents of H, halo, C _1-6 alkyl and C _1-6 alkoxy and R ⁶ is H or C _1-6 alkyl; R ⁴ is C _1-6 alkyl, C _3-10 cycloalkyl, halo, -CF ₃ or C _1-6 alkoxy-C _1-6 alkyl; and R ⁵ H or C _1-6 alkyl. The compound of claim 2, wherein -XY- is -C(R ⁴ )=N- or -N=C(R ⁴ )-; Z-system-(CH(R ² )) _n -(CH(R ^2A ) _m -; n and m are 1 to 3; R ² is H or C _1-6 alkyl; R ^2A is H or C _1-6 alkyl; R ¹ is H, F, Br, pyridyl, OH-phenyl or -C≡C-CH ₂ OH; R ³ system Wherein R ⁷ is selected from a substituent consisting of H, F, Br, Cl, and -OCH ₃ , or R ⁷ is independently selected from two substituents of Cl and F, and wherein R ⁶ is H, Methyl or ethyl; R ⁴ is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, Br, -CF ₃ or methoxyethyl; and R ⁵ H or ethyl. The compound of claim 1 which is selected from the group consisting of: A pharmaceutical composition for treating a disease modulated by phosphodiesterase 10 comprising an effective amount of at least one compound of claim 1 in a pharmaceutically acceptable carrier. A use of a compound according to claim 1 for the manufacture of a medicament for the treatment of a disease modulated by phosphodiesterase 10. a compound of formula II, Or a pharmaceutically acceptable salt thereof, wherein p is 1, 2 or 3; R ¹¹ is H or C _1-6 alkyl; R ^{12 is} independently H or C _1-6 alkyl; R ¹³ is selected from pyridine, pyr Oxazine, , versus a group consisting of; R ¹⁴ is H or C _1-6 alkyl; R ¹⁵ is independently selected from H, halo, C _1-6 alkyl, C _1-6 alkoxy, -CF ₃ , C _{1- 6} alkoxy-C _1-6 alkoxy, OH, hydroxy C _1-6 alkyl, -OCF ₃ , -C(O)OC _1-6 alkyl, -C(O)N(R ¹⁴ ) ₂ , 1 or 2 substituents of the group consisting of -N(R ¹⁴ ) ₂ , -C _1-6 alkyl N(R ¹⁴ ) ₂ , CN and trimethyldecylalkyl; R ¹⁶ is independently selected from H, halo , C _1-6 alkyl, C _1-6 alkoxy, -CF ₃ , C _1-6 alkoxy-C _1-6 alkoxy, OH, hydroxy C _1-6 alkyl, -OCF ₃ , -C(O)OC _1-6 alkyl, -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ ) ₂ , -C _1-6 alkyl N(R ¹⁴ ) ₂ , CN, -SR 1, 2 or 3 substituents of the group consisting of ¹⁴ and trimethyldecane; R ¹⁷ is independently selected from H, halo, C _1-6 alkyl, C _1-6 alkoxy, -CF ₃ , C _1-6 alkoxy-C _1-6 alkoxy, OH, hydroxy C _1-6 alkyl, -OCF ₃ , -OC _3-10 cycloalkyl, -C(O)OC _1-6 alkyl a group consisting of -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ ) ₂ , -C _1-6 alkyl N(R ¹⁴ ) ₂ , CN, -SR ¹⁴ and trimethyldecyl 1 or 2 substituents; and R ¹⁸ H, C _1-6 alkyl, halo, -CF ₃ or C _1-6 alkoxy-C _1-6 alkyl. The compound of claim 7, wherein p is 2 or 3; R ¹¹ is H or C _1-6 alkyl; R ¹² is H or C _1-6 alkyl; R ¹³ is R ¹⁵ is independently selected from one or two substituents of H, halo, C _1-6 alkyl and C _1-6 alkoxy; R ¹⁴ is H or C _1-6 alkyl; R ¹⁶ and R ^{17 is} each H; and R ¹⁸ is C _1-6 alkyl or -CF ₃ . The compound of claim 8, wherein: p is 2 or 3; R ¹¹ is H; R ¹² is H or methyl; and R ¹³ is Wherein R ¹⁵ is H and R ¹⁴ is methyl; R ¹⁶ and R ^{17 are} each H; and R ¹⁸ is tributyl or -CF ₃ . The compound of claim 7 which is selected from the group consisting of: A pharmaceutical composition for treating a disease modulated by phosphodiesterase 10 comprising an effective amount of at least one compound of claim 7 in a pharmaceutically acceptable carrier. A use of a compound according to claim 7 for the manufacture of a medicament for the treatment of a disease modulated by phosphodiesterase 10.